The various types of cholesterols (free, long chain fatty acid-type, and ester-type), found in a variety of tissues and in blood, are primarily biosynthesized in the liver. Free cholesterol biosynthesized in the liver binds to very low-density lipoprotein (VLDL), and is metabolized by lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in blood into low-density lipoprotein (LDL) via intermediate density lipoprotein (IDL). IDL is incorporated into peripheral cells via the LDL receptor and plays an important role in the in-vivo constitution of the cell membrane.
However, LDL is oxidized by cells, such as vascular endothelial cells, various chemical and physical factors, and other factors such as heat, resulting in the generation of modified LDL, which is also referred to as “oxidized LDL”, in blood. Since the vascular flow normally contains a sufficient amount of antioxidants, oxidized LDL is hardly generated therein. Even when oxidized LDL is generated, most of it is metabolized in the liver.
On the other hand, oxidized LDL is produced in the vascular endothelium and vascular wall through chemical modifications due to cell-independent actions, such as the action of Fe3+, as well as chemical modifications by cells, such as vascular endothelial cells and macrophages. However, unlike that generated in the vascular flow, oxidized LDL generated in the vascular endothelium and vascular wall accumulates within macrophages.
The accumulation of oxidized LDL in macrophages results due to the incorporation of oxidized LDL, generated as described above, into cells via the cell surface scavenger receptor on macrophages, which serves as a receptor for various modified LDLs (oxidized LDL, acetyl LDL, succinyl LDL, and malondialdehyde LDL) (Nature, Vol. 343, p. 531-535, 1990; Nature, Vol. 343, p. 570-572, 1990; Proc. Natl. Acad. Sci. USA, Vol. 87, p. 9133-9137, 1990; Proc. Natl. Acad. Sci. USA, Vol. 87, p. 8810-8814, 1990; Curr. Opin. Lipodol., Vol. 2, p. 295-300, 1991; and J. Clin. Invest., Vol. 90, p. 1450-1457, 1992).
Unlike the LDL receptor, the macrophage scavenger receptor is not down regulated in an intracellular cholesterol-dependent manner. Thus, macrophages migrating into the vascular endothelium or vascular wall take in a large quantity of modified LDL and accumulate a large quantity of cholesterol to become “foamy cells” (See section 4 “Inflammatory Cells: 1. Scavenger Receptor” in “The molecular atherosclerology”, pp. 249-258, 1995, Medical Review Co.).
The above-mentioned macrophages, that creep into the vascular endothelium or vascular wall, originally derive from macrophages that migrate from the vascular flow in response to oxidized LDL generation signals generated at various sites, such as in the vascular flow, vascular endothelium, and vascular wall. Specifically, such macrophage accumulation is based on the following characteristics of oxidized LDL; its chemotactic effect on macrophages and monocytes in the vascular flow; the accumulation of monocytes and macrophages on vascular endothelial cells; the induction of the migration of the accumulated monocytes and macrophages into the vascular endothelium and vascular wall; the induction of the differentiation of migrated monocytes into macrophages; and the suppression of the migration of completely differentiated macrophages.
A recently identified oxidized LDL receptor (also referred to as the Ox-LDL Receptor and LOX-1; Nature, Vol. 386, p. 73-77, 1997; Biochemical Study on Lipids, Vol. 39, p. 83-84, 1997; Genomics, Vol. 54, No. 2, p. 191-199, 1998; Biochem. J., Vol. 339, Part 1, p. 177-184, 1999; Biochem. J., Vol. 330, Part 3, p. 1417-1422, 1998) expressed on the surface of vascular endothelial cells has been demonstrated to be deeply involved in such accumulations of monocytes and macrophages on vascular endothelial cells.
Earlier studies demonstrated that the intracellular production of nitrogen monoxide (NO) is inhibited by the oxidized LDL receptor-mediated incorporation of oxidized LDL into vascular endothelial cells from the vascular flow, which results in the expression of cell adhesion molecules on the surface of vascular endothelial cells. This suggests that the expression of cell adhesion molecules results in the entrapment of macrophages and monocytes on vascular endothelial cells, and then the entrapped macrophages and monocytes migrate into the vascular endothelium and vascular wall. Then, the macrophages in the vascular endothelium and vascular wall presumably become “foamy cells”, due to the macrophage scavenger receptor-mediated incorporation of oxidized LDL, as described above.
The conversion of macrophages to foamy cells in the vascular wall is a major cause of arteriosclerosis. Thus, the above-mentioned accumulation of monocytes and macrophages in the vascular endothelial cells is believed to trigger the onset of arteriosclerosis.
Intensive research has been made into the biological function of oxidized LDL receptor (LOX-1), which is deeply involved in the accumulation of monocytes and macrophages on vascular endothelial cells, and its involvement in various diseases. Recent studies have reported the following:                (1) The expression level of LOX-1 is markedly higher in arteriosclerotic lesions (Circulation, Vol. 99, No. 24, p. 3110-3117, 1999);        (2) The expression level of LOX-1 is higher in the high blood-pressure rat model (Biochem. Biophys. Res. Conmun., Vol. 237, No. 3, p. 496-498, 1997);        (3) Shear stress increases the expression level of LOX-1 (Circ. Res., Vol. 83, No. 3, p. 328-333, 1998);        (4) LOX-1 is expressed in macrophages as well as in vascular endothelial cells and the expression levels are elevated following TNFα stimulation (FEBS Lett., Vol. 440, No. 1-2, p. 29-32, 1998);        (5) The expression level of LOX-1 is elevated by angiotensin II (Circ. Res., Vol 84, No 9, p. 1043-1049, 1999; Circulation, Vol. 100, No. 9, p. 899-902, 1999); and        (6) Not only oxidized LDL, but also in-vivo spodogenous cells, such as apoptotic cells (cells programmed to die through apoptosis), senescent erythrocytes, and activated blood platelets, are incorporated into cells via the oxidized LDL receptor (LOX-1) (Proc. Natl. Acad. Sci. USA., Vol. 95, p. 9535-9540, 1998; Proc. Natl. Acad. Sci. USA., Vol. 97, No. 1, p. 360-364, 2000).        
Previously reported antibodies against human oxidized LDL receptor (LOX-1) were all derived from non-human mammals only. No report has been published on the preparation of human monoclonal antibodies or on therapeutic approaches for various diseases using such human monoclonal antibodies.